Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8) GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC50: 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC50: 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

Examination of surface properties and in vitro biological performance of amorphous diamond-like carbon-coated polyurethane

Despite the emerging use of diamond-like carbon (DLC) as a coating for medical devices, few studies have examined the resistance of DLC coatings onto medical polymers to both microbial adherence and encrustation. In this study, amorphous DLC of a range of refractive indexes (1.7-1.9) and thicknesses (100-600 nm) was deposited onto polyurethane, a model polymer, and the resistance to microbial adherence (Escherichia coli; clinical isolate) and encrustation examined using in vitro models. In comparison to the native polymer, the advancing and receding contact angles of DLC-coated polyurethane were lower, indicating greater hydrophilic properties. No relationship was observed between refractive index, thickness, and advancing contact angle, as determined using multiple correlation analysis. The resistances of the various DLC-coated polyurethane films to encrustation and microbial adherence were significantly greater than that to polyurethane; however, there were individual differences between the resistances of the various DLC coatings. In general, increasing the refractive index of the coatings (100 nm thickness) decreased the resistance of the films to both hydroxyapatite and struvite encrustation and to microbial adherence. Films of lower thicknesses (100 and 200 nm; of defined refractive index, 1.8), exhibited the greatest resistance to encrustation and to microbial adherence. In conclusion, this study has uniquely illustrated both the microbial antiadherence properties and resistance to urinary encrustation of DLC-coated polyurethane. The resistances to encrustation and microbial adherence were substantial, and in light of this, it is suggested that DLC coatings of low thickness and refractive index show particular promise as coatings of polymeric medical devices. (c) 2006 Wiley Periodicals, Inc.